Alzheimer's disease (AD) is a debilitating neurocognitive disorder that is characterized by an insidious onset and progressive course of memory decline and deficits in other cognitive domains, such as working memory. Recently, AD research has focused on the preclinical detection and treatment of the disease, as earlier detection and intervention may allow us to halt or slow AD pathogenesis. Previous research has identified working memory difficulties in early symptomatic AD, suggesting that changes in this cognitive domain may precede or co-occur with episodic memory impairment. Using resting and task-based activation and connectivity on functional magnetic resonance imaging (fMRI) is a novel way to characterize the brain markers and mechanisms that underpin working memory performance in preclinical AD. Neuropsychological measures of working memory may reveal only subtle behavioral differences between individuals with preclinical AD and healthy adults, but task and resting fMRI activation and connectivity in working-memory related networks may be able to identify aberrant patterns that distinguish individuals at risk for AD. It is possible that network disruption in working memory-related areas may also moderate the observed relation between AD brain pathology (cortical amyloid-beta and medial temporal lobe tau) and episodic memory performance in the preclinical stage of AD. This project will investigate (1) working memory-related task fMRI activation and connectivity in preclinical ADAD; (2) the relation between working memory, episodic memory, and AD brain pathology in preclinical ADAD and sporadic AD; and (3) resting-state brain network integrity in working memory-related networks and its relations to AD brain pathology in preclinical sporadic AD and preclinical autosomal dominant Alzheimer's disease (ADAD). Aim 1 will draw on young, cognitively unimpaired mutation carriers and non-carrier family members from the Colombian ADAD kindred; carriers of this mutation (presenilin1 E280A) are virtually guaranteed to develop dementia due to AD by their late 40s. Aims 2 and 3 will similarly recruit Colombian kindred carriers and non-carriers, as well as cognitively normal older adults at risk for sporadic AD based on elevated molecular markers of AD pathology see on positron emission tomography (PET) in the brain. Through this project the applicant will (1) gain expertise in imaging and neuropsychological methods related to investigating the neural correlates of working memory in preclinical ADAD and preclinical sporadic AD, (2) receive training and mentorship on experimental design pertaining to cognitive and imaging research on neurodegenerative diseases, and (3) establish professional relationships with experienced researchers and collaborators who will equip him with the skills to transition to career independence.